Type 2 diabetes as an inflammatory disease

Components of the immune system are altered in obesity and type 2 diabetes (T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes. These immunological changes include altered levels of specific cytokines and chemokines, changes in the number and activation state of various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support this notion and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease.     

Type 2 diabetes as a lipid disorder

Diabetic dyslipidemia is a cluster of plasma lipid and lipoprotein abnormalities that are metabolically interrelated. The recognition that the elevation of large VLDL 1 particles initiates a sequence of events that leads to the formation of small dense LDL and HDL species has focused the assembly of VLDL particles on the spotlight as a potential culprit of dyslipidemia. Notably dyslipidemia is associated with insulin resistance, visceral obesity and liver fat content. Insulin resistance is associated with excessive flux of substrates for VLDL assembly to the liver as well as the upregulation of the machinery generating large VLDL particles in excess. The regulation of different molecular steps in this cascade of events are complex and so far poorly understood. The disordered crosstalk between adipose tissue and the liver results in an imbalance of the machinery that orchestrates the regulation of VLDL production. A number of studies indicates that adipocytokines in particular adiponectin may be a seminal player in the regulation of fat metabolism in the liver. Future discoveries hopefully will delineate the regulatory steps to allow more targeted treatment of diabetic dyslipidemia.     

Genetic variants entail type 2 diabetes as an innate immune disorder

Type 2 Diabetes (T2D) is characterized by alteration in the circulatory levels of key inflammatory proteins, where our body strives to eliminate the perturbing factor through inflammation as a final resort to restore homeostasis. Plasma proteins play a crucial role to orchestrate this immune response. Over the past two decades, rigorous genetic efforts taken to comprehend T2D physiology have been partially successful and have left behind a dearth of knowledge of its causality. Here, we have investigated how the reported genetic variants of T2D are associated with circulatory levels of key plasma proteins. We identified 99 T2D genetic variants that serve as strong pQTL (protein Quantitative Trait Loci) for 72 plasma proteins, of which 4 proteins namely Small nuclear ribonucleoprotein F [SNRPF] (p = 2.99 × 10⁻¹⁴), Platelet endothelial cell adhesion molecule [PECAM1] (p = 1.9 × 10⁻⁴⁵), Trypsin-2 [PRSS2] (p = 7.6 × 10⁻⁴³) and Trypsin-3 [PRSS3] (p = 5.7 × 10⁻⁸) were previously not reported for association to T2D. The genes that encode these 72 proteins were observed to be highly expressed in at least one of the four T2D relevant tissues - liver, pancreas, adipose and whole blood. Comparative analysis of interactions of the studied proteins amongst these four tissues revealed distinct molecular connectivity. Assessment of biological function by gene-set enrichment highlighted innate immune system as the lead process enacted by the identified proteins (FDR q = 3.7 × 10⁻¹⁶). To validate the findings, we analyzed Coronary Artery Disease (CAD) and Rheumatoid Arthritis (RA) individually and as expected, we observed innate immune system as a top enriched pathway for RA but not for CAD. Our study illuminates strong regulation of plasma proteome by the established genetic variants of T2D.     

Vitiligo as an inflammatory skin disorder: a therapeutic perspective

From a therapeutic standpoint, vitiligo is still regarded by many physicians as a simple problem of regenerative medicine, with the main aim to repopulate the depigmented skin with functional melanocytes from the margins of the lesions or from intact progenitors in hair follicles. However, recent research in vitiligo suggests that various local triggers alert the skin immune innate system and may precede adaptive immune responses targeting melanocytes. This scenario is close to that of other common skin inflammatory disorders like psoriasis and atopic, and suggests to target as a priority this clinically silent inflammatory component of he disease. This perspective highlights possible targets for intervention.     

Type 2 diabetes: an atherothrombotic syndrome

Insulin resistance is found in around 80-90% of subjects with older onset (type 2) diabetes and in approximately 25% of the general population. Insulin resistance prior to the development of frank type 2 diabetes and type 2 diabetes itself is associated with a significant increase in the risk of atherothrombotic disease, which is due in part to a disruption in the balance of factors regulating coagulation and fibrinolysis. Both insulin resistance and type 2 diabetes are associated with the development of endothelial dysfunction, and enhanced platelet aggregation and activation. Whilst the plasma levels of many clotting factors including fibrinogen, FVII, FVIII, FXII, FXIII b-subunit are elevated, the fibrinolytic system is relatively inhibited as a consequence of an increase in plasminogen activator inhibitor type-1 (PAI-1) levels. These changes favour the development of a hypercoagulable pro-thrombotic state, which may in turn enhance cardiovascular risk by increasing the likelihood of developing an occlusive thrombus within a coronary/cerebral artery, and/or contributing to the development of atherosclerotic lesions. This article reviews the current published evidence of the pro-thrombotic changes that occur in association with type 2 diabetes and insulin resistance, and the putative underlying mechanisms which lead to these changes.     

Reactive oxygen species-selective regulation of aortic inflammatory gene expression in Type 2 diabetes

Vascular diseases are a major complication of diabetes mellitus (DM), although their etiology is poorly understood. NADPH oxidase-derived reactive oxygen species (ROS) production and inflammation are potential mediators of DM-associated vascular diseases. Using db/db mice as a Type 2 diabetes model, we examined the relationship between NADPH oxidase-derived ROS and vascular inflammation. When compared with control m+/+ mice, aortas from 4- and 12-wk-old db/db mice had higher NADPH oxidase activity and increased superoxide levels, leading to NADPH oxidase-dependent impaired vasodilation at 12 wk. Diabetes progression from 4 to 12 wk led to increased Nox1, Nox4, and p22(phox) subunit mRNAs and induced the expression of a group of matrix remodeling-related cytokines: connective tissue growth factor (CTGF), bone morphogenetic protein 4 (BMP-4), and osteopontin (OPN). After 8 wk of treatment with the superoxide scavenger Tempol, 12-wk-old db/db mice had lower superoxide production, reduced plasma glucose and lipids, and lower BMP-4 and OPN protein expression when compared with nontreated mice. No changes were observed with Tempol in CTGF or m+/+ mice. The ability of Tempol to reverse ROS production as well as OPN and BMP-4, but not CTGF, induction suggests that DM-induced vascular inflammation involves both ROS-sensitive and -insensitive pathways.     

Type 2 diabetes and cardiovascular disease: getting to the fat of the matter

The increasing national prevalence of obesity is a major public health concern and a substantial burden on the health care resources of Canada. In addition to the direct health impact of obesity, this condition is a well-established risk factor for the development of various prevalent comorbidities including type 2 diabetes, hypertension, and cardiovascular disease. Historically, adipose tissue has been regarded primarily as an organ for energy storage. However, the discovery of leptin in the mid 1990's revolutionized our understanding of this tissue and has focused attention on the endocrine function of adipose tissue as a source of secreted bioactive peptides. These compounds, collectively termed adipokines, regulate a number of biological functions including appetite and energy balance, insulin sensitivity, lipid metabolism, blood pressure, and inflammation. The physiological importance of adipokines has led to the hypothesis that changes in the synthesis and secretion of these compounds in the obese are a causative factor contributing to the development of obesity and obesity-related diseases in these individuals. Following from this it has been proposed that pharmacologic manipulation of adipokine levels may provide novel effective therapeutic strategies to treat and prevent obesity, type 2 diabetes, and cardiovascular disease.     

Type 2 diabetes mellitus as risk factor for colorectal cancer

Colorectal cancer occurs more frequently in patients with type 2 diabetes mellitus. The hyperinsulinemia-hypothesis suggests that elevated levels of insulin and free IGF-1 promote proliferation of colon cells and lead to a survival benefit of transformed cells, ultimately resulting in colorectal cancer. In patients with type 2 diabetes mellitus, epidemiological studies show an increased risk for colorectal cancer and an even higher risk if patients are treated with sulphonylureas or insulin. Moreover, tumour progression at hyperinsulinemia is more rapid and tumour-associated mortality is increased. Colorectal cancer can be avoided by screening. Recommendations for colorectal cancer screening should employ the recent epidemiologic evidence. All patients with type 2 diabetes mellitus should be recommended to undergo colonoscopy before starting insulin therapy, and screening intervals should not exceed 5 years. For this concept, a review of the evidence is presented, and a screening algorithm for colorectal cancer in patients with type 2 diabetes mellitus is proposed.     

L-cysteine supplementation as an adjuvant therapy for type-2 diabetes

Diabetes remains a major public health issue. According to the American Diabetes Association, 23.5 million, or 10.7% of people in the USA aged 20 years and older, have diabetes. Type-2 diabetes is treated both by controlling the diet and with oral hypoglycemic drugs. However, for many patients, achieving a tight control of glucose is difficult with current regimens. This chapter discusses a relatively low-cost dietary supplement that could be used as an adjuvant therapy for type-2 diabetes. A review of the literature indicates that cysteine-rich whey protein improves glucose metabolism in diabetic animals and type-2 diabetic patients. Similarly, in animal studies, improvement in glucose metabolism is observed after supplementation with L-cysteine, or molecules containing a cysteine moiety. This chapter discusses the biochemical mechanisms by which L-cysteine can upregulate the insulin-dependent signaling cascades of glucose metabolism. Further studies are needed to examine whether clinical interventions using L-cysteine as an adjuvant therapy indeed help to control glycemia and vascular inflammation in the diabetic patient population.     

Adiponectin represents an independent cardiovascular risk factor predicting serum HDL-cholesterol levels in type 2 diabetes

Low levels of high-density lipoprotein (HDL)-cholesterol represent an independent cardiovascular risk factor and, besides reduced physical activity, mechanisms leading to decreased HDL-cholesterol levels are not known. We aimed to test the hypothesis, that adiponectin provides a missing link between type 2 diabetes and low levels of HDL-cholesterol, independent from common metabolic risk factors. 523 patients with type 2 diabetes were investigated for adiponectin serum levels and parameters of lipid metabolism. Even after correction for age, gender, BMI and fasting insulin concentration, serum levels of adiponectin were highly significant (P<0.0001) and positively (regression analysis: r=0.86) associated with HDL-cholesterol levels in type 2 diabetes. CONCLUSION: adiponectin seems to predict HDL-cholesterol levels in patients with diabetes mellitus type 2. Low levels of adiponectin are associated with low levels of HDL-cholesterol independently from common metabolic risk factors and therefore represent an independent cardiovascular risk factor in type 2 diabetes. Thus, adiponectin is a potentially new drug target in the treatment of dyslipidaemia.     

Apoptosis as an instrument in cardiovascular development

Cell death as a phenomenon in embryonic development was first described over 100 years ago. Approximately 30 years ago the process was named apoptosis, and its involvement is now recognized in many life processes, in virtually every animal species, and from fertilization to the death of an organism. In cardiovascular development, it coincides with major developmental processes in specific time windows. Both intrinsic (controlled by mitochondrial activity) and extrinsic (starting with death receptors) apoptotic pathways co-regulate developmental mechanisms. During cardiac development, many cell populations are recruited to the heart, where they differentiate into cardiomyocytes, fibroblasts, smooth muscle cells, endocardial and endothelial cells lining the inner surfaces, and epicardial cells lining the outer contours. In particular, neural crest-derived cell populations, which migrate to specific locations in the heart, are prone to apoptosis. During the complex geometric changes that occur in the primary heart tube and connected vessel segments, proper interaction of the respective cell populations guarantees the ensuing steps of differentiation. Growth factors, including endothelin, VEGF, and TGF-beta, as well as other factors, such as FasL, play dominant roles in these phases. Transgenic and knockout studies have provided strong evidence for aberrant patterns of apoptosis resulting in congenital malformations and syndromic malformations, including septation anomalies, interrupted aortic arch segments, coronary anomalies, and DiGeorge syndrome. Embryonic remodeling of the arterial system, including the coronary arteries, is accompanied by apoptosis patterns, the disruption of which results in severe malformations. It is interesting to note that hemodynamic factors, such as flow-driven shear stress, regulate the expression of genes that are important for signaling molecules such as endothelin and NO-synthase. In general, high shear stress protects against apoptosis, thus preventing the onset of disease processes in the fully-grown vasculature, and regulating the remodeling of the vascular system in the embryo.     

Role of inflammatory mechanisms in pathogenesis of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is characterized by progressive β‐cell dysfunctioning and insulin resistance. This article reviews recent literature with special focus on inflammatory mechanisms that provoke the pathogenesis of T2DM. We have focused on the recent advances in progression of T2DM including various inflammatory mechanisms that might induce inflammation, insulin resistance, decrease insulin secretion from pancreatic islets and dysfunctioning of β‐cells. Here we have also summarized the role of various pro‐inflammatory mediators involved in inflammatory mechanisms, which may further alter the normal structure of β‐cells by inducing pancreatic islet's apoptosis. In conclusion, it is suggested that the role of inflammation in pathogenesis of T2DM is crucial and cannot be neglected. Moreover, the insight of inflammatory responses in T2DM may provide a new gateway for the better treatment of diabetes mellitus. J. Cell. Biochem. 114: 525–531, 2013. © 2012 Wiley Periodicals, Inc.     

Fulminant Type 1 diabetes in a pregnant woman as an initial manifestation of the insulin autoimmune syndrome

Diabet. Med. 29, 1335-1338 (2012) ABSTRACT: Fulminant Type 1 diabetes is a subtype of Type 1 diabetes characterized by (1) abrupt onset of diabetes, (2) very short duration of hyperglycaemia with mildly elevated HbA(1c) (相似文献